Matrix metalloproteinase-2 & progressive cardiac fibrosi

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DESCRIPTION (provided by applicant): Persistent dysfunctional remodeling of the heart as a response to injury represents a final common pathway resulting in ventricular failure and death. Changes in the proliferative capacity and extracellular matrix synthetic profile of the cardiac fibroblast component of the heart are primarily responsible for these events. These changes in the cardiac fibroblast phenotype are driven by conditions and peptide factors commonly present within the failing heart, including tissue hypoxia and enhanced release of pro-fibrotic peptides, such as angiotensin II, endothelin-1 and Interleukin-1 . Ventricular remodeling is also associated with enhanced synthesis of several matrix metalloproteinases, of which MMP-2 (gelatinase A) may be of central importance. The primary hypothesis of this proposal is that enhanced synthesis of gelatinase A in response to ischemic injury and pro-fibrotic peptides directly drives the dysfunctional changes in cardiac fibroblast phenotypes responsible for progressive cardiac failure. This proposal will examine the transcriptional regulation of gelatinase A in response to angiotensin II, endothelin-1 and Interleukin-1 to define critical enhancer elements and transcription factors that drive high level synthesis of this enzyme in the heart. The validity of these transcriptional regulatory mechanisms will be directly tested in a genomic context using transgenic gelatinase A mice containing defined mutations in specific enhancer elements. Finally, the ability of gelatinase A as an individual agent to induce dysfunctional ventricular remodeling will be tested in vivo using targeted gene expression in the heart. These studies should provide key insights into the role of a specific matrix metalloproteinase in the cardiac response to injury and could provide the pathophysiologic basis for the development of new forms of therapy for this disabling condition.